Angiogenesis is the formation of new blood vessels from existing blood vessels. To initiate the angiogenic process, biochemical signals stimulate protease secretion from, among other cell types, endothelial cells lining the lumen of the vessel. The secreted proteases degrade the basement membrane and the endothelial cell layer protrudes through the hole created in the basement membrane. If the biochemical signals are continuously present, the migrating endothelial cells undergo mitosis and divide. The dividing cells form a sprout through the vessel wall. Again, if the angiogenic stimulus remains, the sprouts merge to form capillary loops which later mature into new blood vessels.
Under normal circumstances of wound healing, fetal and embryonic development and formation of the corpus luteum, endometrium and placenta, the initial angiogenic signals subside and other, secondary, signals predominate to turn off the angiogenic process. However in disease states such as cancer, angiofibroma, neovascular glaucoma, arteriovenous malformations, nonunion fractures, arthritis and other connective tissue disorders, Osler-Weber syndrome, atherosclerotic plaques, psoriasis, corneal graft neovascularization, pyogenic granuloma, retrolental fibroplasia, diabetic retinopathy, scleroderma, hemangioma, trachoma, vascular adhesions and hypertrophic scars, the local concentration of angiogenic signals never decreases and new blood vessels continuously form, supplying the diseased tissue with nutrients. This allows the tumor or diseased tissue to grow.
In cancer, undesired angiogenesis provides a steady supply of nutrients to the tumor. This allows the tumor to grow as well as metastasize. However, in addition to a general tumor growth-supporting role, some tumors are highly angiogenic. For example, Kaposi's Sarcoma (KS) is a tumor characterized by unregulated growth of blood vessels. It is, in fact, an angiogenic tumor. Currently, the treatment of Kaposi's Sarcoma, like most tumors, is based on chemotherapy. However, most chemotherapeutic agents are universally harmful to all dividing cells; cancerous or not. Thus, there is a need for compounds that will reduce the angiogenesis required for many disease states, including cancer and specifically, Kaposi's Sarcoma. This invention surprising meets these and other needs.